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Mol Cell Biol DOI:10.1128/MCB.01372-13

Residual complexes containing SMARCA2 (BRM) underlie the oncogenic drive of SMARCA4 (BRG1) mutation.

Publication TypeJournal Article
Year of Publication2014
AuthorsWilson, BG, Helming, KC, Wang, X, Kim, Y, Vazquez, F, Jagani, Z, Hahn, WC, Roberts, CWM
JournalMol Cell Biol
Volume34
Issue6
Pages1136-44
Date Published2014 Mar
ISSN1098-5549
KeywordsAdenosine Triphosphatases, Animals, Carcinogenesis, Cell Line, Cell Line, Tumor, Cell Proliferation, Chromatin Assembly and Disassembly, Chromosomal Proteins, Non-Histone, DNA Helicases, Fibroblasts, Humans, Mice, Mutation, Nuclear Proteins, Transcription Factors
Abstract

Collectively, genes encoding subunits of the SWI/SNF (BAF) chromatin remodeling complex are mutated in 20% of all human cancers, with the SMARCA4 (BRG1) subunit being one of the most frequently mutated. The SWI/SNF complex modulates chromatin remodeling through the activity of two mutually exclusive catalytic subunits, SMARCA4 and SMARCA2 (BRM). Here, we show that a SMARCA2-containing residual SWI/SNF complex underlies the oncogenic activity of SMARCA4 mutant cancers. We demonstrate that a residual SWI/SNF complex exists in SMARCA4 mutant cell lines and plays essential roles in cellular proliferation. Further, using data from loss-of-function screening of 165 cancer cell lines, we identify SMARCA2 as an essential gene in SMARCA4 mutant cancer cell lines. Mechanistically, we reveal that Smarca4 inactivation leads to greater incorporation of the nonessential SMARCA2 subunit into the SWI/SNF complex. Collectively, these results reveal a role for SMARCA2 in oncogenesis caused by SMARCA4 loss and identify the ATPase and bromodomain-containing SMARCA2 as a potential therapeutic target in these cancers.

URLhttp://mcb.asm.org/cgi/pmidlookup?view=long&pmid=24421395
DOI10.1128/MCB.01372-13
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24421395?dopt=Abstract

Alternate JournalMol. Cell. Biol.
PubMed ID24421395
PubMed Central IDPMC3958034
Grant ListR01CA172152 / CA / NCI NIH HHS / United States
R01 CA113794 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R01 CA172152 / CA / NCI NIH HHS / United States
R01CA113794 / CA / NCI NIH HHS / United States